Synthesis of substituted p-stereogenic vinylphosphine oxides by olefin cross-metathesis

Article abstract of DOI:10.1021/ol035011m

(Matrix presented) Substituted vinylphosphine oxides have been prepared in good yield and exclusive (E)-olefin selectivity via olefin cross-metathesis using Grubbs and Hoveyda-type ruthenium catalysts. In addition, metathesis of chiral vinylphosphine oxid

Full text of DOI:10.1021/ol035011m

ORGANIC
LETTERS
2003
Vol. 5, No. 18
3217-3220
Synthesis of Substituted P-Stereogenic
Vinylphosphine Oxides by Olefin
Cross-Metathesis
Oleg M. Demchuk,† K. Michał Pietrusiewicz,*,†,‡ Anna Michrowska,† and
,†
Karol Grela*
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52,
01-224 Warsaw, Poland, and Department of Organic Chemistry, Maria
Curie-Skłodowska UniVersity, Gliniana 33, 20-614 Lublin, Poland
grela@icho.edu.pl; michal@hermes.umcs.lublin.pl
Received June 5, 2003
ABSTRACT
Substituted vinylphosphine oxides have been prepared in good yield and exclusive (E)-olefin selectivity via olefin cross-metathesis using
Grubbs and Hoveyda-type ruthenium catalysts. In addition, metathesis of chiral vinylphosphine oxides proceeds without racemization of the
phosphorus chirality center, providing easy access to functionalized chiral nonracemic (E)-alkenylphosphine oxides.
Achiral and chiral vinyl phosphine oxides have found wide
use as versatile synthetic intermediates in the preparation of
various mono- and diphosphorus systems.1 Development of
an easy access to their terminally substituted and function-
alized homologues would greatly expand their synthetic
utility.
Some examples have recently appeared in the literature
which have shown that metathesis2 can be used to access
some phosphor-substituted olefins. Methods for the synthesis
of vinylphosphonates via an olefin metathesis reaction have
been recently published by Grubbs, Hanson, and Hayes.3
Allylphosphonates and allylphosphoramides have been cy-
clized in ring-closing metathesis reaction (RCM) by Hanson
et al.4 Gouverneur and co-workers have demonstrated the
intramolecular RCM of allylic phosphine oxides, phosphi-
nates, and phosphine-boranes.5 However, to the best of our
knowledge, intermolecular cross-metathesis (CM) reactions
of vinylphosphine oxides have not been previously reported.
In this communication, we report the single-step synthesis
of â-functionalized R,â-unsaturated phosphine oxides cata-
lyzed by the ruthenium metathesis catalysts.
Although the second-generation ruthenium complex 1a
possesses in general a very good application profile,2 the
phosphine-free catalyst 1b, recently introduced by Hoveyda
et al.,6 displays even higher reactivity toward some electron-
deficient substrates such as acrylonitrile,7 fluorinated olefins,8
and vinyl sulfones.9 Excellent air stability, ease of storage
and handling, and the possibility of catalyst reuse are
† Polish Academy of Sciences.
‡ Maria Curie-Skłodowska University.
(1) (a) Sasse, K. Houben Weyl Methoden der Organischen Chemie;
Thieme Verlag: Stuttgart, 1963; Vol. 12/1. (b) Pietrusiewicz, K. M.;
Zabłocka, M. Chem. ReV. 1994, 94, 1375. (c) Pietrusiewicz, K. M.;
Zabłocka, M.; Wis´niewski, W. Phosphorus, Sulfur, Silicon 1990, 49/50,
263.
(2) Pertinent review: (a) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res.
2001, 34, 18. (b) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012. (c)
Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413. (d) Schuster, M.;
Blechert, S. Angew. Chem., Int. Ed. Engl. 1997, 36, 2037.
(3) (a) Chatterjee, A. K.; Choi, T.-L.; Grubbs, R. H. Synlett 2001, 1034.
(b) For an olefin CM approach to vinylphosphonate-linked nucleic acids,
cf.: Lera, M.; Hayes, C. J. Org. Lett. 2001, 3, 2765. (c) For a RCM reaction
of P-chiral vinyl- and allylphosphonamides and phosphonates, see: Stoiano-
va, D. S.; Hanson, P. R. Org. Lett. 2000, 2, 1769.
(4) (a) Hanson, P. R.; Stoianova, D. S. Tetrahedron Lett. 1998, 39, 3939.
(b) Hanson, P. R.; Stoianova, D. S. Tetrahedron Lett. 1999, 40, 3297. (c)
Sprott, K. T.; Hanson, P. R. J. Org. Chem. 2000, 65, 7913.
(5) (a) Bujard, M.; Gouverneur, V.; Mioskowski, C. J. Org. Chem. 1999,
64, 2119. (b) Trevitt, M.; Gouverneur, V. Tetrahedron Lett. 1999, 40, 7333.
(c) Hetherington, L.; Greedy, B.; Gouverneur, V. Tetrahedron 2000, 56,
2053. (d) Schuman, M.; Trevitt, M.; Redd, A.; Gouverneur, V. Angew.
Chem., Int. Ed. 2000, 39, 2491.
(6) (a) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J.; Hoveyda,
A. H. J. Am. Chem. Soc. 1999, 121, 791. (b) Garber, S. B.; Kingsbury, J.
S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 8168.
10.1021/ol035011m CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/07/2003

additional advantages of this system.6 In this investigation,
we decided to utilize two Hoveyda-type ruthenium com-
plexes (1c,d) recently developed in our laboratory.10,11
Catalyst 1d, very stable and easy to prepare from inexpensive
substrates, shows activity comparable to the parent Hoveyda
carbene 1b,10 while the nitro-substituted catalyst 1c possesses
a dramatically enhanced reactivity, e.g., 1c promotes me-
tathesis even at 0 °C.11
extend our investigation to a more diverse set of olefinic
substrates. The results compiled in Tables 1 and 2 illustrate
Table 1. Substituted Vinylphosphine Oxides 4 by
Cross-Metathesis of Diphenyl(vinyl)phosphine Oxide 3a
Scheme 1. Grubbs 1a and Hoveyda-type 1b-d
Second-Generation Ruthenium Olefin Metathesis Catalysts
Test reactions between olefin 2a (1 equiv), diphenyl-
(vinyl)phosphine oxide 3a (2 equiv), and complexes 1a and
1c,d (0.05 equiv) were performed under argon, at reflux
temperature in dichloromethane (Procedure A). All the
“second-generation” ruthenium complexes effect the forma-
tion of corresponding product 4a in similarly good yields
(78-82%) and exclusively as the (E)-isomer (Scheme 2).
a Isolated yields of analytically pure products. Procedure A: 2 (1 equiv),
3a (2 equiv). Procedure B: 2 (2.5 equiv), 3a (1 equiv). Reaction conditions:
catalyst 1a-d (5 mol %), dichloromethane, reflux, 16 h. b Yield based on
NMR.
the scope and synthetic utility of this reaction. Thus, the
olefinic substrates bearing various functionalities, including
chloro- and bromoalkenes, carbonyl compounds, and NH-
unprotected indole can be easily converted to the corre-
sponding R,â-unsaturated phosphine oxides in good yields.
In all reported cases, the (E)-isomer was the only phosphine
oxide product detected by HPLC or NMR.
Scheme 2. Screening of the Catalytic Activity of 1a, 1c, and
1d in the Cross-Metathesis of 3a
Table 2. Synthesis of P-Chiral Phosphine Oxides 416
a Isolated yields of analytically pure products.
These results indicate that, in this particular case, the
Hoveyda-type carbenes are not superior to the Grubbs
catalyst 1a.
Having identified ruthenium complexes 1a, 1c, and 1d as
effective catalysts for this transformation, we decided to
(7) Randl, S.; Gessler, S.; Wakamatsu, H.; Blechert, S. Synlett 2001,
430.
(8) Imhof, S.; Randl, S.; Blechert, S. Chem. Commun. 2001, 1692.
(9) (a) For a CM reaction of phenyl vinyl sulfone catalyzed by 1a, see:
Grela, K.; Bieniek, M. Tetrahedron Lett. 2001, 42, 6425. (b) For screening
of the catalytic performance of Ru- and Mo-based catalysts in this
transformation, see: Grela, K.; Michrowska, A.; Bieniek, M.; Kim, M.;
Klajn, R. Tetrahedron 2003, 59, 4525-4531.
a Phosphine oxide 3b (ref 17): [R]D20 -80.5 (c 1, CH2Cl2), ee 98%,
absolute configuration SP. Phosphine oxide 3c (ref 18): [R]20 -57.2 (c 1,
CH2Cl2); ee 73%, absolute configuration RP. b Isolated yields Dof analytically
pure products. Reaction conditions: 2 (2.5 equiv), 3 (1 equiv), catalyst 1a-d
(5 mol %), dichloromethane, reflux, 16 h. c Homodimer 5 (85%) was
isolated instead of the expected product 4j.
(10) Grela, K.; Kim, M. Eur. J. Org. Chem. 2003, 963.
(11) (a) Grela, K.; Harutyunyan, S.; Michrowska, A. Angew. Chem., Int.
Ed. 2002, 41, 4038. (b) For applications of 1c, see ref 9b and: Ostrowski,
S.; Mikus, A. Mol. DiVers. Accepted for publication.
3218
Org. Lett., Vol. 5, No. 18, 2003

When the CM alkene partner 2 is inexpensive or easily
available, it is reasonable to use it in excess, allowing the
more economical utilization of vinylphosphine oxides 3a-c
(Procedure B). The excess of alkenes 2b,c or their “dimer-
ization” products can be easily removed by evaporation under
vacuum or by flash chromatography.
of their metathetic conversions into functionalized terminally
substituted analogues retaining the resolved P-stereogenic
center, as well as the unsaturation functionality, would give
a new impetus to the synthesis of novel elaborated P-
stereogenic systems of diversified structures. Access to
enantiopure vinyl phosphine oxides possessing substituents
at the double bond has been so far very limited.1b
As summarized in Table 2,16 various substituted chiral
vinylphosphine oxides can be accessed by CM reaction of
homochiral 3b and 3c. More electron-deficient alkene 2j gave
a somewhat unexpected result, as after column chromatog-
raphy, an 85% yield of homodimer 5 was obtained instead
of the expected cross-product 4j. It should be noted that in
previous reactions with 3a-c (Procedure B), we have not
observed formation of their homodimers.19 The examples of
homometathesis between two electron-deficient olefins are
rare, and good yields have only been reported for ho-
modimerization of acrylates20 and for cross-metathesis of
R,â-unsaturated substrates with styrenes.21 To check if the
presence of the fluoroolefin 2j was necessary for the
formation of 5, we refluxed a CH2Cl2 solution of phosphine
oxide 3b in the presence of 5 mol % 1c, and after the
reaction, we isolated the product 5 in high yield and
exclusively as the (E)-isomer (Scheme 4). This finding
It has been reported by Grubbs that CM of terminal olefins
and 2-methyl-2-butene (2f) constitutes a very elegant method
of an allyl to prenyl conversion.12 However, when an
electron-deficient substrate (such as acrylate) is used, another
reaction pathway has been observed, leading to the prefer-
ential formation of methyl-substituted olefin.12 Similarly, in
the reaction of vinylphosphine oxide 3a and neat 2-methyl-
2-butene (bp 35-38 °C), we observed a highly chemo- and
stereoselective formation of the (1E)-prop-1-enyl phosphine
oxide 4f (98% purity by NMR). It should be noted, however,
that when the same reaction was performed in a 1:1 mixture
of 2-methyl-2-butene:CH2Cl2, increased amounts of di-
methyl-substituted product 4g were formed (Scheme 3).
Scheme 3. Cross-Metathesis of Vinylphosphine Oxide 3a and
2-Methyl-2-butene
Scheme 4. Homodimerization of 3b
In connection with our ongoing research program aimed
at the preparation of new chiral phosphine ligands, we next
decided to test the CM of P-stereogenic13 vinylphosphine
oxides 3b,c. In recent years, resolved vinyl phosphine oxides
have served as convenient precursors to P-stereogenic
ligands14 as well as chiral reagents for effecting P to C
chirality transfer in stoichiometric addition, cycloaddition,
and substitution processes.15 The straightforward possibility
provides a potentially useful method for preparing chiral
bidentate phosphine ligands.
(16) General Procedure for Cross-Metathesis of Vinylphosphine
Oxides. Procedure B. To a mixture of vinylphosphine oxide 3 (0.5 mmol)
and 2 (1.25 mmol) in CH2Cl2 (4 mL) was added a solution of catalyst 1
(0.025 mmol, 5 mol %) in CH2Cl2 (1 mL). The resulting mixture was stirred
at 45 °C for 16 h. The solvent was removed under reduced pressure. The
crude product 4 was purified by flash chromatography (hexane-acetone
4:1, then hexane-ethyl acetate-methanol 5:2:0.5). (RP)-(-)-tert-Butyl-
(phenyl)[(1E)-3-phenylprop-1-enyl]phosphine oxide (4l): pale gray crys-
(12) Chatterjee, A. K.; Sanders, D. P.; Grubbs, R. H. Org. Lett. 2002, 4,
1939.
(13) Frequently, the terms “P-chiral” and “P-chirogenic” have been used
to differentiate chiral phosphorus-containing compounds that bear a
stereogenic phosphorus atom from those that do not. These terms are,
however, incorret, and their use should be discouraged. We thank Prof.
Scott E. Denmark for bringing this issue to our attention.
tals (72% of yield); [R]2D0 - 27.6 (c 1, CH2Cl2); mp 103-104 °C; IR (KBr,
cm-1) 2961, 1943, 1732, 1668, 1628, 1603, 1495, 1476, 1436, 1364, 1268,
1213, 1213, 1171, 1110, 997, 816, 776, 748, 699; 31P NMR (CDCl3, 202,
1
MHz) δ ) 38.8; H NMR (CDCl3, 500 MHz) δ ) 7.72-7.16 (m, 10 H,
(14) (a) Johnson, C. R.; Imamoto, T. J. Org. Chem. 1987, 52, 2170. (b)
Bianchini, C.; Cicchi, S.; Peruzzini, M.; Pietrusiewiez, K. M.; Brandi, A.
J. Chem. Soc., Chem. Commun. 1995, 833. (c) Nagel, U.; Roller, C. Z.
Naturforsch. B 1998, 53, 221. (d) Pietrusiewicz, K. M.; Zabłocka, M.
Tetrahedron Lett. 1988, 29, 1991. (e) Maj, A. M.; Pietrusiewicz, K. M.;
Suisse, I.; Abgossou, F.; Mortreux, A. Tetrahearon: Asymmetry 1999, 10,
831. (f) Maj, A. M.; Pietrusiewicz, K. M.; Suisse, I.; Abgossou, F.; Mortreux,
A. J. Organomet. Chem. 2001, 626, 157.
(15) (a) Brandi, A.; Cannavo, P.; Pietrusiewicz, K. M.; Zabłocka, M.;
Wieczorek, W.J. Org. Chem. 1989, 54, 3073. (b) Brandi, A.; Cicchi, S.;
Goti, A.; Pietrusiewicz, K. M. Tetrahedron Lett. 1991, 32, 3265. (c) Brandi,
A.; Cicchi, S.; Goti, A.; Pietrusiewicz, K. M. Tetrahdedron: Asymmetry
1991, 2, 1063. (d) Katagiri, N.; Yamamoto, M.; Iwaoka, T.; Kaneko, C. J.
Chem. Soc., Chem. Commun. 1991, 1429. (e) Brandi, A.; Cicchi, S.; Goti,
A.; Pietrusiewicz, K. M.; Zabłocka, M.; Wis´niewski, W. J. Org. Chem.
1991, 56, 4383. (f) Brandi, A.; Cicchi, S.; Goti, A.; Pietrusiewicz, K. M.
Phosphorus, Sulfur, Silicon 1993, 75, 155. (g) Cardellicchio, C.; Fiandanese,
V.; Naso, F.; Pacifico, S.; Koprowski, M. Pietrusiewicz, K. M. Tetrahedron
Lett. 1994, 35, 6343.
Ph), 7.07 (tt, J ) 16.9, 6.3 Hz, 1 H, CH2-CH), 6.23 (ddt, J ) 26.9, 16.9,
1.7 Hz, 1 H, P(O)-CH), 3.63 (dt, J ) 6.3, 1.9 Hz, 2 H, Ph-CH2), 1.09 (d,
J ) 14.9 Hz, 9 H, C-(CH3)3); 13C NMR (CDCl3, 126 MHz) δ ) 151.7 (s,
CH2-CH), 137.8 (s, CH2-C), 131.8 (d, J ) 8 Hz, o-C in Ph-P(O)), 131.3
(d, J ) 2.6 Hz, p-C in Ph-P(O)), 130.8 (d, J ) 92.8 Hz, P(O)-C), 128.9
(s, o-C in Ph-CH2), 128.6 (s, m-C in PhCH2), 128.1 (d, J ) 10.9 Hz, m-C
in Ph-P(O)), 126.6 (s, p-C in Ph-CH2), 119.1 (d, J ) 91.5 Hz, CH-
P(O)), 40.8 (d, J ) 15.5 Hz, CH2), 32.6 (d, J ) 73.3 Hz, C(CH3)3), 24.2
(s, C(CH3)3); MS (ESI) m/z rel intensity) 299 (70) [M + H]+, 321 (100)
[M + Na]+; HR-MS (C19H23OPNa): calcd 321.1379, found 321.1391.
(17) Pietrusiewicz, K. M.; Zabłocka, M.; Monkiewicz, J. J. Org. Chem.
1984, 49, 152.
(18) Pietrusiewicz, K. M. Phosphorus, Sulfur, Silicon 1996, 109, 573.
The optically pure oxide 3c has been available, but for the sake of a more
reliable comparison of enantiomeric purities of the substrate and the product
1
by means of NMR using chiral shift reagents, which in these cases gave
only moderate line separations (ca. 4-5 Hz, refs 22 and 23), the
enantiomeric purity of the starting 3b was deliberately lowered to 73% by
admixing of rac-3b.
Org. Lett., Vol. 5, No. 18, 2003
3219

To prove that the metathesis of P-stereogenic vinylphos-
phine oxides proceeds without racemization at the phospho-
rus chirality center, we subjected the resultant vinylphosphine
Similarly, in the case of homodimerization of 3b, careful
NMR inspection of the reaction mixture revealed that only
one diastereoisomer of 5 was formed in this transformation.
In conclusion, we have shown that the substituted vi-
nylphosphine oxides can be prepared in good yield and
exclusive (E)-olefin selectivity via olefin cross-metathesis
using Grubbs and Hoveyda-type ruthenium catalysts. The
metathesis of P-stereogenic vinylphosphine oxides proceeds
without racemization of a chiral phosphorus center, providing
easy access to functionalized chiral nonracemic (E)-al-
kenylphosphine and bis(phosphine) oxides. These findings
further expand the range of olefins that participate in CM
reaction. Experiments to broaden the scope of this reaction
for the preparation of phosphine ligands are under way.
1
oxides to 31P and H NMR experiments with Kagan’s shift
reagent.22 Careful inspection of the NMR spectra revealed
that no racemization takes place and that the ee values of
substrates 3b,c and of products 4h,l are virtually identical.23
(19) In homodimerization reaction of 3b, we have also isolated a
theoretical yield (≈5%) of the phosphine oxide 6, a product of CM between
3b and catalyst 1c.
Acknowledgment. The authors wish to thank Prof.
Holger Butenscho¨n, Universita¨t Hannover, for helpful sug-
gestions and Dr. Bohdan Kamien´ski for his assistance in
NMR data collection. This work was supported by the State
Committee of Scientific Research (Grant No. 4T09A13622).
(20) Choi, T.-L.; Lee, C. W.; Chatterjee, A. K.; Grubbs, R. H. J. Am.
Chem. Soc. 2001, 123, 10417.
(21) Chatterjee, A. K.; Toste, F. D.; Choi, T.-L.; Grubbs, R. H. AdV.
Synth. Catal. 2002, 344, 634.
(22) (a) Pakulski, Z.; Demchuk, O. M.; Kwiatosz, R.; Osin´ski, P. W.;
SÄwierczyn´ska, W.; Pietrusiewicz, K. M. Tetrahedron: Asymmetry 2003,
14, 1459. (b) Deshmukh, M.; Dunach, E.; Juge, S.; Kagan, H. B.
Tetrahedron Lett. 1984, 25, 3467.
(23) Optical purities were calculated from the corresponding 31P and 1H
NMR spectra registered in the presence of (S)-N-[1-(1-naphthyl)ethyl]-3,5-
dinitrobenzamide (cf. Supporting Information). E.g., 4l: 31P NMR (CDCl3,
202 MHz): δ (rel weight) ) 39.30 (1.00), 39.25 (0.15); significant fragments
of the 1H NMR spectrum (CDCl3, 500 MHz): δ (rel weight) ) 6.29 (0.15),
6.27 (1.00); 6.26 (0.16), 6.24 (1.00); 6.20 (0.17), 6.19 (1.00); 1.10 (0.14),
1.08 (1.00); 1.07 (0.16), 1.05 (1.00). Calculated optical purity: 72 ( 4%
ee.
Supporting Information Available: Experimental pro-
cedures and characterization data for all products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL035011M
3220
Org. Lett., Vol. 5, No. 18, 2003